Perioperative Medicine  |   October 2016
Preclinical Pharmacology of CW002: A Nondepolarizing Neuromuscular Blocking Drug of Intermediate Duration, Degraded and Antagonized by l-cysteine—Additional Studies of Safety and Efficacy in the Anesthetized Rhesus Monkey and Cat
Author Notes
  • From the Department of Anesthesiology, Weill Medical College of Cornell University, New York, New York (H.S., J.J.S., P.M.H., M.R.B., M.T.M., J.K.M., P.M.S., B.J.P.); Cedarburg Pharmaceuticals, A Division of Albany Molecular Research, Inc., Grafton, Wisconsin (J.D.M.); Department of Chemistry, Concordia University, Mequon, Wisconsin (S.G.V.O.); Animal Resources Facility, Albany Medical Center, Albany, New York (E.J.); and Impact Pharmaceutical Services, Inc., Research Triangle Park, North Carolina (E.A., G.W.C.). Current affiliation: Department of Anesthesiology, Jikei University School of Medicine, Nishishimbashi, Minatoku, Tokyo, Japan (H.S.).
  • Submitted for publication May 5, 2015. Accepted for publication June 21, 2016.
    Submitted for publication May 5, 2015. Accepted for publication June 21, 2016.×
  • Address correspondence to Dr. Savarese: Department of Anesthesiology, Weill Medical College of Cornell University, 525 East 68th Street, New York, New York 10065. jjsavare@med.cornell.edu. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Perioperative Medicine / Basic Science / Neuromuscular Diseases and Drugs / Pharmacology / Radiological and Other Imaging / Technology / Equipment / Monitoring
Perioperative Medicine   |   October 2016
Preclinical Pharmacology of CW002: A Nondepolarizing Neuromuscular Blocking Drug of Intermediate Duration, Degraded and Antagonized by l-cysteine—Additional Studies of Safety and Efficacy in the Anesthetized Rhesus Monkey and Cat
Anesthesiology 10 2016, Vol.125, 732-743. doi:10.1097/ALN.0000000000001254
Anesthesiology 10 2016, Vol.125, 732-743. doi:10.1097/ALN.0000000000001254
Abstract

Background: CW002, a novel nondepolarizing neuromuscular blocking agent of intermediate duration, is degraded in vitro by l-cysteine; CW002-induced neuromuscular blockade (NMB) is antagonized in vivo by exogenous l-cysteine.1  Further, Institutional Animal Care and Use Committee–approved studies of safety and efficacy in eight anesthetized monkeys and six cats are described.

Methods: Mean arterial pressure, heart rate, twitch, and train-of-four were recorded; estimated dose producing 95% twitch inhibition (ED95) for NMB and twitch recovery intervals from 5 to 95% of baseline were derived. Antagonism of 99 to 100% block in monkeys by l-cysteine (50 mg/kg) was tested after bolus doses of approximately 3.75 to 20 × ED95 and after infusions. Vagal and sympathetic autonomic responses were recorded in cats. Dose ratios for [circulatory (ED20) or autonomic (ED50) changes/ED95 (NMB)] were calculated.

Results: ED95s of CW002 in monkeys and cats were 0.040 and 0.035 mg/kg; l-cysteine readily antagonized block in monkeys: 5 to 95% twitch recovery intervals were shortened to 1.8 to 3.6 min after 3.75 to 10 × ED95 or infusions versus 11.5 to 13.5 min during spontaneous recovery. ED for 20% decrease of mean arterial pressure (n = 27) was 1.06 mg/kg in monkeys; ED for 20% increase of HR (n = 27) was 2.16 mg/kg. ED50s for vagal and sympathetic inhibition in cats were 0.59 and >>0.80 mg/kg (n = 14 and 15). Dose ratios for [circulatory or autonomic changes/ED95 (NMB)] were all more than 15 × ED95.

Conclusions: The data further verify the neuromuscular blocking properties of CW002, including rapid reversal by l-cysteine of 100% NMB under several circumstances. A notable lack of autonomic or circulatory effects provided added proof of safety and efficacy.